Evidence map›Paper›PMID 27592162›Full record

ArticleBiochimica et biophysica acta. General subjects2017

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.

C A Maile, J R Hingst, K K Mahalingan, A O O'Reilly, M E Cleasby, J R Mickelson, M E McCue, S M Anderson, T D Hurley, J F P Wojtaszewski and 1 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biochimica et biophysica acta. General subjects, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
2.4field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 23 citations in OpenAlex.

  1. Article
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  7. Myopathies Related to Glycogen Metabolism Disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2018
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 5 institutions in 3 countries.

C A MaileComparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, UK.
J R HingstDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
K K MahalinganDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA.
A O O'ReillySchool of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, UK.
M E CleasbyDepartment of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
J R MickelsonVeterinary Biomedical Sciences Department, University of Minnesota, St. Paul, MN, USA.
M E McCueVeterinary Population Medicine Department, University of Minnesota, St. Paul, MN, USA.
S M AndersonVeterinary Population Medicine Department, University of Minnesota, St. Paul, MN, USA.
T D HurleyDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA.
J F P WojtaszewskiDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
R J PiercyComparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, UK. Electronic address: rpiercy@rvc.ac.uk.
Royal Veterinary College · GBUniversity of Minnesota · USIndiana University School of MedicineUniversity of Copenhagen · DKLiverpool John Moores University · GB

Funding

SMALL MOLECULE INHIBITION OF GLYCOGEN STORAGE AS THERAPY FOR GLYCOGENOSESR01DK027221 · NIDDK · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI HURLEY, THOMAS D. · 1986 to 2020
$4.4M
Structural Determinants of Glycogen Synthase RegulationR01DK079887 · NIDDK · INDIANA UNIVERSITY INDIANAPOLIS · PI HURLEY, THOMAS D. · 2011 to 2014
$1.4M
Regulation of Glycogen Metabolism: Insights from Novel Genetic ModelsK08AR055713 · NIAMS · UNIVERSITY OF MINNESOTA · PI MCCUE, MOLLY E · 2009 to 2013
$644k
NIAMS NIH HHS K08 AR055713NIDDK NIH HHS R01 DK027221NIDDK NIH HHS R01 DK079887
6 · The paper itself

Abstract

backgroundEquine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle.

methodsEquine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change.

resultsPSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower K

conclusionsElevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. GENERAL SIGNIFICANCE: This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.

Indexed as

Adenylate KinaseAmino Acid SequenceAnimalsBlotting, WesternBreedingEnzyme ActivationGlucose-6-PhosphateGlucose Transporter Type 4GlycogenGlycogen Storage DiseaseGlycogen SynthaseGlycogen Synthase Kinase 3 betaHorsesKineticsModels, MolecularMuscle, SkeletalAdenylate KinaseGlucose-6-PhosphateGlucose Transporter Type 4GlycogenGlycogen SynthaseGlycogen Synthase Kinase 3 betaMutant ProteinsProtein SubunitsUridine Diphosphate GlucoseGlycogenGlycogen storage diseaseGlycogen synthaseMusclePolyglucosanPSSM1

Identifiers

PMID27592162
PMCPMC5148651
OpenAlexW2511683920

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.